Nociceptive Scores Research Articles

The effect of central administration of alpha-pinene on capsaicin-induced dental pulp nociception.

To assess the effects of central administration of α-pinene alone and in combination with either bicuculline or naloxone, as GABAA and μ-opioid receptor antagonists, respectively, on capsaicin-induced dental pulp stimulation in rats. Forty-eight adult male Wistar rats aged 2months (230-270g) were cannulated via their lateral ventricles for the central administration of the drugs. α-Pinene was injected at 0.1, 0.2 and 0.4μmolL-1 . Then, dental pulp stimulation was induced by intradental application of capsaicin solution (100μg), and nociceptive scores were recorded for up to 40min. For investigation of the anti-inflammatory effects of α-pinene, expression of COX-2 in the subnucleolus caudalis (Vc) of rats was determined using immunofluorescence staining. Nonparametric repeated measure Friedman and Kruskal-Wallis tests as well as parametric one-way analysis of variance were used for the statistical analysis. α-Pinene at 0.2 and 0.4μmolL-1 was able to decrease capsaicin-induced nociception. Moreover, there was a significant increase in the expression of COX-2-positive cells in the Vc of capsaicin-treated rats (P<0.01). This effect was prohibited by α-pinene (0.4μmolL-1 ). Co-administration of bicuculline (1μg per rat) or naloxone (6μg per rat) with α-pinene (0.4μmolL-1 ), however, prevented the inhibitory effects of α-pinene on both capsaicin-induced pulp nociception and COX-2 over-expression. Pinene exhibited significant curable effects on capsaicin-induced pulpal nociception and inflammation mainly via pharmacological interfacing with GABAA and μ-opioid receptors.

The effect of intracerebroventricular injection of CGRP on pain behavioral responses and monoamines concentrations in the periaqueductal gray area in rat.

Objective(s):Calcitonin gene related peptide (CGRP) receptors are widely distributed in the central nervous system. The aim of this study was to investigate the effects of intracerebroventricular (ICV) injection of CGRP on pain behavioral responses and on levels of monoamines in the periaqueductal gray area (PAG) during the formalin test in rats.Materials and Methods:Twenty-four male rats were studied in four groups (n=6). CGRP was injected into the left cerebral ventricle (1.5 nmol, 5 µl). After 20 min, formalin (2.5%) was subcutaneously injected into the right hind paw. Behavior nociceptive score was recorded up to 60 min. During the formalin test, the PAG was subjected to microdialysis and levels of norepinephrine, 3-methoxy-4-hydroxyphenyl-glycol (HMPG), dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin and 5-hydroxyindole-acetic acid (HIAA) were measured by HPLC.Results:ICV injection of CGRP lead to a significant pain reduction in acute, middle and chronic phases of the formalin test. Dialysate concentrations of norepinephrine, HMPG, dopamine, DOPAC, serotonin and HIAA in the PGA area showed an increase in acute phase, middle phase and beginning of the chronic phase of the formalin test.Conclusion:CGRP significantly reduced pain by increased concentrations of monoamines and their metabolites in dialysates from PAG when injected ICV to rats.

Analgesic and anti-inflammatory effects of resveratrol in rat models of pain: Any role in clinical pain management?

Background: Resveratrol (RSV) is a biomolecule that has been demonstrated in numerous studies to possess therapeutic potentials with multiple targets. Despite the reported low bioavailability, it could exhibit novel role in clinical pain management. Objective: To investigate the systemic analgesic and anti-inflammatory effects of RSV in comparison to diclofenac and etoricoxib. Materials and Methods: Following institutional ethics approval, the study was conducted in the physiology research laboratory. The animals (42 male Wistar rats) used were divided into seven groups (n = 6) in separate cages. Chemical pain was evaluated using formalin-induced nociception test. Statistical analysis was done using analysis of variance and Kruskal–Wallis statistical tests. Results: There is a significant change in nociceptive score in the early phase; however, no significant changes in the late phase in the formalin test. Anti-inflammatory studies showed that RSV 50 mg/kg has a significantly potent anti-inflammatory effect when compared to control, but similar in activity to etoricoxib. Tumor necrosis factor alpha and interleukin-2 concentration did not significantly differ between the groups. Conclusion: RSV may elicit its analgesic actions by inhibiting the direct activation of nociceptors. It may be suggested that systemic RSV at a dose of 50 mg/kg in Wistar rats significantly reduces inflammation comparable to etoricoxib, but possibly less potent than diclofenac. Thus, RSV may be useful in the management of acute and chronic pain with significant inflammatory components. Further broad based human clinical studies on the analgesic and anti-inflammatory properties of resveratrol are required to confirm its potential role in clinical pain management.

Comparison of paravertebral blockade techniques with and without ultrasound guidance in calves.

OBJECTIVE To compare the effectiveness of an ultrasound-guided paravertebral nerve blockade technique (UGPNB) with distal and proximal paravertebral nerve blockade techniques without ultrasound guidance (DPNB and PPNB, respectively) in calves. ANIMALS 4 calf cadavers and 7 healthy calves. PROCEDURES A suitable acoustic window was identified to facilitate access to the T13, L1, and L2 spinal nerves in cadavers and live calves. In cadavers, nerves were injected with dye under ultrasound guidance. In calves, the UGPNB, DPNB, and PPNB were performed in random order at 10-day intervals by injection of an anesthetic solution containing 2% lidocaine hydrochloride. Nociceptive withdrawal responses were assessed to determine the effects of the blockades. RESULTS In cadavers, nerve staining success rates (ie, ≥ 2-cm-long dye path) achieved with ultrasound guidance were 88% (T13 [ventral branch]), 75% (T13 and L1 [dorsal branches] and L1 and L2 [ventral branches]), and 38% (L2 [dorsal branch]). The nerves were each identified as a hyperechoic band in a longitudinal plane. In calves, the UGPNB, DPNB, and PPNB reduced the withdrawal response to the noxious stimulus, mainly in the dorsal-cranial, dorsal-caudal, and ventral-cranial areas of the flank. Overall, the UGPNB resulted in a better nociceptive cumulative score, administering only one half of the local anaesthetic dose, compared with findings for the DPNB and PPNB. However, time to perform the UGPNB was longer. CONCLUSIONS AND CLINICAL RELEVANCE The UGPNB evaluated may be an improved alternative to the DPNB and PPNB for provision of anesthesia for flank surgery in calves. However, effectiveness of the UGPNB should be evaluated in a clinical setting and in adult cattle.

Experimental study of nanostructured sorption capacity of the sorbent as adsorbent in dressings

To determine a dexmedetomidine concentration, to be added to an alfaxalone-based bath solution, that will enhance the anaesthetic and analgesic effects of alfaxalone; and to compare the quality of anaesthesia and analgesia provided by immersion with either alfaxalone alone or alfaxalone with dexmedetomidine in oriental fire-bellied toads (Bombina orientalis).Pilot study followed by a prospective, randomized, experimental trial.Fourteen oriental fire-bellied toads.The pilot study aimed to identify a useful dexmedetomidine concentration to be added to an anaesthetic bath containing 20 mg 100 mL-1 alfaxalone. Thereafter, the toads were assigned to one of two groups, each comprising eight animals, to be administered either alfaxalone (group A) or alfaxalone–dexmedetomidine (group AD). After immersion for 20 minutes, the toads were removed from the anaesthetic bath and the righting, myotactic and nociceptive reflexes, cardiopulmonary variables and von Frey filaments threshold were measured at 5 minute intervals and compared statistically between groups. Side effects and complications were noted and recorded.In the pilot study, a dexmedetomidine concentration of 0.3 mg 100 mL-1 added to the alfaxalone-based solution resulted in surgical anaesthesia. The toads in group AD showed higher von Frey thresholds and lower nociceptive withdrawal reflex scores than those in group A. However, in group AD, surgical anaesthesia was observed in two out of eight toads only, and induction of anaesthesia was achieved in only 50% of the animals, as compared with 100% of the toads in group A.The addition of dexmedetomidine to an alfaxalone-based solution for immersion anaesthesia provided some analgesia in oriental fire-bellied toads, but failed to potentiate the level of unconsciousness and appeared to lighten the depth of anaesthesia. This limitation renders the combination unsuitable for anaesthetizing oriental fire-bellied toads for invasive procedures.

Alfaxalone versus alfaxalone–dexmedetomidine anaesthesia by immersion in oriental fire-bellied toads (Bombina orientalis)

ObjectiveTo determine a dexmedetomidine concentration, to be added to an alfaxalone-based bath solution, that will enhance the anaesthetic and analgesic effects of alfaxalone; and to compare the quality of anaesthesia and analgesia provided by immersion with either alfaxalone alone or alfaxalone with dexmedetomidine in oriental fire-bellied toads (Bombina orientalis). Study designPilot study followed by a prospective, randomized, experimental trial. AnimalsFourteen oriental fire-bellied toads. MethodsThe pilot study aimed to identify a useful dexmedetomidine concentration to be added to an anaesthetic bath containing 20 mg 100 mL-1 alfaxalone. Thereafter, the toads were assigned to one of two groups, each comprising eight animals, to be administered either alfaxalone (group A) or alfaxalone–dexmedetomidine (group AD). After immersion for 20 minutes, the toads were removed from the anaesthetic bath and the righting, myotactic and nociceptive reflexes, cardiopulmonary variables and von Frey filaments threshold were measured at 5 minute intervals and compared statistically between groups. Side effects and complications were noted and recorded. ResultsIn the pilot study, a dexmedetomidine concentration of 0.3 mg 100 mL-1 added to the alfaxalone-based solution resulted in surgical anaesthesia. The toads in group AD showed higher von Frey thresholds and lower nociceptive withdrawal reflex scores than those in group A. However, in group AD, surgical anaesthesia was observed in two out of eight toads only, and induction of anaesthesia was achieved in only 50% of the animals, as compared with 100% of the toads in group A. Conclusions and clinical relevanceThe addition of dexmedetomidine to an alfaxalone-based solution for immersion anaesthesia provided some analgesia in oriental fire-bellied toads, but failed to potentiate the level of unconsciousness and appeared to lighten the depth of anaesthesia. This limitation renders the combination unsuitable for anaesthetizing oriental fire-bellied toads for invasive procedures.

Noxious Stimulation of the Rat Tooth Pulp May Impair Learning and Memory Through the Induction of Hippocampal Apoptosis.

To determine whether noxious stimulation of the rat tooth pulp induces learning and memory impairment through the induction of apoptosis in the hippocampus. Thirty-five adult rats were divided randomly into five groups (each n=7) as follows: control, sham-operated, sham-vehicle, capsaicin-treated, and capsaicin plus ibuprofen-treated group. After preparing dental cavities via cutting 2 mm of the distal extremities of the mandibular incisors, polyethylene crowns were placed on the teeth. Based on the study groups, different injections were administered into the cavities. Nociceptive scores for each block were obtained by measuring the number of seconds that the animal spent rubbing and flicking the lower jaw. After recording the nociceptive behaviors, spatial learning and memory were assessed by using the Morris Water Maze (MWM) test. The hippocampal levels of Bcl-2, Bax, and caspase-3 protein were determined by immunoblotting. Statistical analyses were performed using one- or two-way analysis of variance. Noxious pulp stimulation induced by intradental application of capsaicin significantly increased time and traveled distance in the MWM test. Capsaicin stimulation of the pulp also significantly increased the Bax:Bcl-2 ratio and activated caspase-3 in the hippocampus (P<.01), which was inhibited by ibuprofen pretreatment (P<.05). Memory and learning impairment induced by noxious stimulation of the rat tooth pulp may be correlated with activation of apoptotic pathways in the hippocampus.

Chemical stimulation of the lateral hypothalamus by carbachol attenuated the formalin-induced pain behaviors in rats

Electrical and chemical stimulation of the lateral hypothalamus (LH) produces analgesia. Previous studies emphasized the importance of LH in the modulation of nociceptive behaviors in the acute pain models. In the current study, for the first time, we examined the effect of direct chemical stimulation of the LH with cholinergic receptor agonist, carbachol, on pain-related behaviors in the formalin test as a model of persistent inflammatory pain. Forty-eight adult male Wistar rats were implanted unilaterally with cannula into the LH. Four doses of carbachol (62.5, 125, 250 and 500nM/0.5μl saline) were microinjected into the LH just 5min before the formalin test. Vehicle group received 0.5μl saline into the LH. Pain-related behaviors were quantified and monitored in 5-min blocks for 60min test period. Average nociceptive scores and area under the curve (AUC) as raw pain scores×time by the linear trapezoidal method were used for the statistical analyses. One important finding of our study was that carbachol blocks the nociceptive responses in both phases of formalin-induced nociception in a dose-dependent manner. Altogether, the percentage decrease of AUC values calculated for treatment groups, compared to the control group, was more significant in the late phase than the early phase. These findings suggest that LH modulates formalin-induced nociception through spinal and/or supraspinal sites.

Effects of COX inhibition and LPS on formalin induced pain in the infant rat.

In the adult, immune and neural processes jointly modulate pain. During development, both are in transition and little is known about the role that the immune system plays in pain processing in infants and children. The objective of this study was to determine if inhibition or augmentation of the immune system would alter pain processing in the infant rat, as it does in the adult. In Experiment 1, rat pups aged 3, 10, or 21 (PN3, PN10, and PN21) days of age were pretreated with NS398 (selective cyclooxygenase (COX)-2 inhibitor) or SC560 (selective COX-1 inhibitor) and tested in the intraplantar formalin test to assess effects of COX inhibition on nociception. Neither drug had an effect on the behavioral response at PN3 or PN10 pups but both drugs attenuated nociceptive scores in PN21 pups. cFos expression in the spinal cord likewise was reduced only at PN21. In Experiment 2, pups were injected with lipopolysaccharide (LPS) prior to the formalin test at PN3 or PN21. LPS increased the nociceptive response more robustly at PN21 than at PN3, while increasing cytokine mRNA equally at both ages. The augmentation of pain responding at PN21 was largely during the late stages of the formalin test, as reported in the adult. These data support previous findings demonstrating late maturing immune modulation of nociceptive behaviors.

The effects of tramadol on norepinephrine and MHPG releasing in locus coeruleus in formalin test in rats: a brain stereotaxic study.

The relationship between tramadol, as an antinociceptive drug, and locus coeruleus (LC), the main noradrenergic nucleus of the brain that affects regulation and modulation of pain through descending noradrenergic pathways was investigated. Male Sprague-Dawley rats were divided into four groups of 10 rats. The rats were fixed in stereotaxic instrument and then a probe was inserted into LC. Pain was induced by subcutaneous injection of 50 μl of 2.5% formalin 40 minutes after initiation of microdialysis in right hind paw, and nociceptive pain scores were calculated every 5 minutes. Subsequently noradrenaline (NA) and its metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), were collected and measured by microdialysis of locus coeruleus in freely moving rats every 15 minutes during formalin injection. Nociceptive pain scores observed in formalin test had the highest nociceptive sensation 5 minutes after injection. Significant rises in concentrations of NA and MHPG, in samples taken between 30 and 45 min after initiation of the locus coeruleus microdialysis, coincided with the peak of the pain after injection of formalin. According to concurrency of the highest nociceptive sensation and peak of NE and MHPG concentrations, tramadol can indirectly affect the LC by blocking the pain signals from different parts of the brain such as periaqueductal gray mater, central nucleus of amygdale or the spinal cord.

Relevance of the cyclophosphamide-induced cystitis model for pharmacological studies targeting inflammation and pain of the bladder

This work aimed at establishing the relevance of using the in vivo model of cyclophosphamide (CYP)-induced bladder inflammation in rats for in vivo pharmacological studies. Specifically, we measured visceral nociception, identified key inflammatory mediators and evaluated the effects of relevant pharmacological treatments. Cystitis was induced in female rats by a single CYP injection. Sensitivity of the lower abdomen to von Frey mechanical stimulation was determined as a nociceptive parameter. Bladders were assessed for weight, wall thickness and macroscopic damage. Inflammatory mediators were quantified in bladders and urines. The effects of aspirin, ibuprofen and morphine were investigated on all these parameters. A single CYP injection increased nociceptive scores and decreased nociceptive threshold in response to mechanical stimuli between 1 and 4h post-administration. Increased bladder weight and wall thickness were associated with edema and hemorrhage. Bladder levels of IL-1β, IL-6, MCP-1 and VCAM, and urinary levels of PGE2 were increased. In contrast, a decrease in the urinary metabolites, indoxyl sulfate and pantothenic acid, was observed. Aspirin, ibuprofen and morphine decreased CYP-induced referred visceral pain. Aspirin and ibuprofen also reversed the increased wall thickness, macroscopic damage and levels of IL-1β, IL-6 and PGE2, and the decreased panthotenic acid levels. In contrast, morphine increased wall thickness, edema, hemorrhage, and bladder IL-6 and MCP-1 levels. This work presents a new and reliable method to evaluate visceral sensitivity in rats, and new relevant biomarkers identified in the bladder and urine to measure inflammation and pain parameters for in vivo pharmacological studies.

Effect of butorphanol on thermal nociceptive threshold in healthy pony foals

Pain management is an important component of foal nursing care, and no objective data currently exist regarding the analgesic efficacy of opioids in foals. To evaluate the somatic antinociceptive effects of 2 commonly used doses of intravenous (i.v.) butorphanol in healthy foals. Our hypothesis was that thermal nociceptive threshold would increase following i.v. butorphanol in a dose-dependent manner in both neonatal and older pony foals. Seven healthy neonatal pony foals (age 1-2 weeks), and 11 healthy older pony foals (age 4-8 weeks). Five foals were used during both age periods. Treatments, which included saline (0.5 ml), butorphanol (0.05 mg/kg bwt) and butorphanol (0.1 mg/kg bwt), were administered i.v. in a randomised crossover design with at least 2 days between treatments. Response variables included thermal nociceptive threshold, skin temperature and behaviour score. Data within each age period were analysed using a 2-way repeated measures ANOVA, followed by a Holm-Sidak multiple comparison procedure if warranted. There was a significant (P<0.05) increase in thermal threshold, relative to Time 0, following butorphanol (0.1 mg/kg bwt) administration in both age groups. No significant time or treatment effects were apparent for skin temperature. Significant time, but not treatment, effects were evident for behaviour score in both age groups. Butorphanol (0.1 mg/kg bwt, but not 0.05 mg/kg bwt) significantly increased thermal nociceptive threshold in neonatal and older foals without apparent adverse behavioural effects. Butorphanol shows analgesic potential in foals for management of somatic painful conditions.

Lumbar facet joint compressive injury induces lasting changes in local structure, nociceptive scores, and inflammatory mediators in a novel rat model.

Objective. To develop a novel animal model of persisting lumbar facet joint pain. Methods. Sprague Dawley rats were anaesthetized and the right lumbar (L5/L6) facet joint was exposed and compressed to ~1 mm with modified clamps applied for three minutes; sham-operated and naïve animals were used as control groups. After five days, animals were tested for hind-paw sensitivity using von Frey filaments and axial deep tissue sensitivity by algometer on assigned days up to 28 days. Animals were sacrificed at selected times for histological and biochemical analysis. Results. Histological sections revealed site-specific loss of cartilage in model animals only. Tactile hypersensitivity was observed for the ipsi- and contralateral paws lasting 28 days. The threshold at which deep tissue pressure just elicited vocalization was obtained at three lumbar levels; sensitivity at L1 > L3/4 > L6. Biochemical analyses revealed increases in proinflammatory cytokines, especially TNF-α, IL-1α, and IL-1β. Conclusions. These data suggest that compression of a facet joint induces a novel model of local cartilage loss accompanied by increased sensitivity to mechanical stimuli and by increases in inflammatory mediators. This new model may be useful for studies on mechanisms and treatment of lumbar facet joint pain and osteoarthritis.

The role of P2X7 purinergic receptors in inflammatory and nociceptive changes accompanying cyclophosphamide‐induced haemorrhagic cystitis in mice

ATP is released in response to cellular damage, and P2X7 receptors have an essential role in the onset and maintenance of pathological changes. Haemorrhagic cystitis (HC) is a well-known adverse effect of therapy with cyclophosphamide used for the treatment of many solid tumours and autoimmune conditions. Here we have evaluated the role of P2X7 receptors in a model of HC induced by cyclophosphamide. Effects of pharmacological antagonism or genetic deletion of P2X7 receptor on cyclophosphamide-induced HC in mice was assessed by nociceptive and inflammatory measures. In addition, the presence of immunoreactive P2X7 receptors was assessed by immunohistochemistry. Pretreatment with the selective P2X7 receptor antagonist A-438079 or genetic ablation of P2X7 receptors reduced nociceptive behaviour scores in the HC model. The same strategies decreased both oedema and haemorrhage indices, on macroscopic or histological evaluation. Treatment with A-438079 decreased the staining for c-Fos in the lumbar spinal cord and brain cortical areas. Treatment with A-438079 also prevented the increase of urinary bladder myeloperoxidase activity and macrophage migration induced by cyclophosphamide and reduced the tissue levels of IL-1β and TNF-α. Finally, P2X7 receptors were markedly up-regulated in the bladders of mice with cyclophosphamide-induced HC. P2X7 receptors were significantly involved in a model of HC induced by cyclophosphamide. Pharmacological inhibition of these receptors might represent a new therapeutic option for this pathological condition.

Antinociceptive effects of intragastric dl-tetrahydropalmatine on visceral and somatic persistent nociception and pain hypersensitivity in rats

Although tetrahydropalmatine (THP), an alkaloid constituent of plants from the genera Stephania and Corydalis, is known to have analgesic property, the antinociceptive effects of THP have not been well evaluated experimentally and the appropriate indications for treatment of clinical pain remain unclear. In the present study, nociceptive and inflammatory models of both somatic and visceral origins were used to assess the antinociceptive and antihyperalgesic effects of intragastric (i.g.) pretreatment of dl-THP in rats. In the bee venom (BV) test that has been well established experimentally, i.g. pretreatment of three doses of dl-THP (20, 40, 60mg/kg, body weight) resulted in less stably antinociceptive effect on the BV-induced persistent paw flinches that are known to be processed by spinal nociceptive circuit, however the drug of the two higher doses produced distinct suppression of the BV-induced persistent nociception rated by nociceptive score that reflects both spinal and supraspinal mediation. Similarly, the antinociception of dl-THP (60mg/kg) was only significant for phase 1 but not for phase 2 of the formalin-induced persistent paw flinches, however, the inhibition was distinct for both phase 1 and phase 2 of the formalin nociceptive score. For the antihyperalgesic effect, in contrast, pretreatment of dl-THP (60mg/kg) produced significant inhibition of both primary hyperalgesia to either thermal or mechanical stimuli and the mirror-image thermal hyperalgesia identified in the BV test. In the acetic acid writhing test, the number of writhes was completely blocked at the first 5-min interval followed by a sustained suppression in the remaining period of the whole time course comparing to the vehicle control.These data suggest that i.g. pre-administration of dl-THP could more effectively inhibit visceral nociception as well as thermal and mechanical inflammatory pain hypersensitivity (hyperalgesia) than persistent nociception. Moreover, the drug is likely to produce more effectiveness on supraspinally processed nociceptive behaviors than spinally mediated nociceptive behaviors, implicating an action of THP at the supraspinal level.

Antinociceptive effect of Allium schoenoprasum L. oral feeding in diabetic rats

Hyperalgesia is considered as one of the marked signs of subchronic diabetes mellitus that could affect the life style of the patients. This study was designed to investigate the antinociceptive effect of chronic feeding of Allium schoenoprasum L. (AS) leaf in streptozotocin-diabetic rats using formalin and hot tail immersion tests. Rats were divided into control, AS leaf-treated control, diabetic, sodium salicylate (SS)-treated diabetic, and AS leaf-treated diabetic groups. The treatment groups received oral administration of AS leaf-mixed pelleted food (3%) for 8 weeks. Finally hyperalgesia were assessed using standard formalin and hot tail immersion tests. AS leaf treatment of diabetic rats reduced pain score in chronic phase of formalin test from 2.41±0.14 to 2.01±0.12 (p<0.05). Regarding hot tail immersion test, diabetic rats showed a significant reduction (5.9s) in tail flick latency as compared to control ones (p<0.05) and AS leaf treatment of diabetic rats did not significantly increase this latency relative to untreated diabetics. Taken together, 8-week administration of AS leaf could attenuate nociceptive score in chronic phase of formalin test in streptozotocin-induced experimental model of diabetes mellitus and has no effect on thermal pain and anti-inflammatory property of the plant is perhaps responsible for its analgesic effect.

Anti-hyperalgesic effect of Mangifera indica L. extract on the sciatic chronic constriction injury model in rats

Context: The aqueous extract of Mangifera indica L. stem bark (MSBE) shows antioxidant, anti-inflammatory and analgesic properties. Aims: To test the MSBE in chronic constriction injury (CCI) of the sciatic nerve in rats, a classical model of neuropathic pain. Methods: Given the possibility that some clinical effect of MSBE can appear only after its chronic administration, we designed a long term medication protocol with 500 mg/kg, p.o. or distilled water daily during 8 days from 9 days post-CCI. Pregabalin (10 mg/kg, p.o.) was used as reference drug. Sham CCI animals received vehicle. Behavioral tests were carried out before CCI, at 9 and 16 days after injury. A section of sciatic nerve, 5 mm distal to the ligature site was dissected for histopathological studies. A single oral similar dose or vehicle was administered to mononeuropathic rats, 14 days after surgery. Mechano-hyperalgesia and thermal hyperalgesia of the ipsilateral paw were determined using a modification of pin prick method and the unilateral hot plate, respectively before CCI, 0, 30, 60, 120 and 180 min post-administration. Results: Repeated oral MSBE doses reduced nociceptive score, increased paw withdrawal latency and attenuated CCI-induced Wallerian degeneration-related changes involved in the hyperalgesic state of CCI rats. Likewise, MSBE shows significant mechanical and thermal anti-hyperalgesic effect from 1h after its single administration. Conclusions: The study of MSBE should be focused in neuropathic pain models since this natural product could have a clinical relevance in the treatment of neuropathic pain syndromes.

Evidence that pregabalin reduces neuropathic pain by inhibiting the spinal release of glutamate

Pregabalin is an anti-convulsant that successfully treats many neuropathic pain syndromes, although the mechanism of its anti-hyperalgesic action remains elusive. This study aims to help delineate pregabalin's anti-hyperalgesic mechanisms. We assessed the effectiveness of pregabalin at decreasing mechanical and cold hypersensitivity induced in a rat model of neuropathic pain. Thus, we compared the effectiveness of pre- or post-treatment with systemic or intrathecal (i.t.) pregabalin at reducing the development and maintenance of the neuropathic pain symptoms. Pregabalin successfully decreased mechanical and cold hypersensitivity, as a pre-treatment, but was less effective at suppressing cold hypersensitivity when administered as a post-treatment. Furthermore, both i.t. and systemic administration of pregabalin were effective in reducing the behavioral hypersensitivity, with the exception of systemic post-treatment on cold hypersensitivity. We also examined pregabalin's effects at inhibiting hind paw formalin-induced nociception in naïve rats and formalin-induced release of excitatory amino acids in the spinal cord dorsal horn (SCDH) both in naïve rats and in rats with neuropathic pain. Pregabalin dose-dependently reduced nociceptive scores in the formalin test. We also present the first evidence that pregabalin reduces the formalin-induced release of glutamate in SCDH. Furthermore, i.t. pregabalin reduces the enhanced noxious stimulus-induced spinal release of glutamate seen in neuropathic rats. These data suggest that pregabalin reduces neuropathic pain symptoms by inhibiting the release of glutamate in the SCDH.

Delayed Onset of Changes in Soma Action Potential Genesis in Nociceptive A-Beta DRG Neurons in Vivo in a Rat Model of Osteoarthritis

BackgroundClinical data on osteoarthritis (OA) suggest widespread changes in sensory function that vary during the progression of OA. In previous studies on a surgically-induced animal model of OA we have observed that changes in structure and gene expression follow a variable trajectory over the initial days and weeks. To investigate mechanisms underlying changes in sensory function in this model, the present electrophysiological study compared properties of primary sensory nociceptive neurons at one and two months after model induction with properties in naïve control animals. Pilot data indicated no difference in C- or Aδ-fiber associated neurons and therefore the focus is on Aβ-fiber nociceptive neurons.ResultsAt one month after unilateral derangement of the knee by cutting the anterior cruciate ligament and removing the medial meniscus, the only changes observed in Aβ-fiber dorsal root ganglion (DRG) neurons were in nociceptor-like unresponsive neurons bearing a hump on the repolarization phase; these changes consisted of longer half width, reflecting slowed dynamics of AP genesis, a depolarized Vm and an increased AP amplitude. At two months, changes observed were in Aβ-fiber high threshold mechanoreceptors, which exhibited shorter AP duration at base and half width, shorter rise time and fall time, and faster maximum rising rate/maximum falling rate, reflecting accelerated dynamics of AP genesis.ConclusionThese data indicate that Aβ nociceptive neurons undergo significant changes that vary in time and occur later than changes in structure and in nociceptive scores in this surgically induced OA model. Thus, if changes in Aβ-fiber nociceptive neurons in this model reflect a role in OA pain, they may relate to mechanisms underlying pain associated with advanced OA.

The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors

Paracetamol analgesic mechanism of action is still poorly defined but mainly involves central inhibition of cyclooxygenases. Here we tested the peripheral antinociceptive effects of paracetamol (intraplantar injections) in a rat model of neuropathic pain. Paracetamol dose-dependently decreased mechanical allodynia and lowered nociceptive scores associated with hyperalgesia testing. These effects were inhibited by the administration of cannabinoid CB(1) (AM251) and CB(2) (AM630) receptor antagonists. The participation of the peripheral cannabinoid system in paracetamol analgesia is suggested.